The long-term goal of this project is to better understand the biology of snail-borne helminth parasites such as Schistosoma mansoni that continue to impose a significant burden or. 'Human health in much of the developing world. We intend to learn how the freshwater snail BiomphalariJrfj/labrata defends itself from infection by S. mansoni and the related trematode, Echinostoma paraensei. By understanding the underlying mechanisms of host defense and parasite infectivity, we will increase the chances of achieving effective new control measures. Another important goal is to develop and maintain expertise in the area of snail-borne pathogens. In this extensively revised proposal, using new methods we have developed, and exploiting powerful tools such as qPCR, microarrays and proteomics, we address three specific aims that relate directly to what have always been the foundation of this research program, snail defenses against trematode infection, and how these are overcome or modified by trematodes. For most of the outlined studies, we emphasize before and after infection comparisons of snails of a particular strain, thus avoiding extraneous variables associated with inter-strain comparisons. For the first aim, we hypothesize that prior exposure to trematode larvae can provoke a state of acquired resistance in B. glabrata. This provides a unique vantage point from which to understand resistance in general, and we propose to compare the responses to trematode challenge of snails with acquired resistance to those of naive snails, to learn how a state of heightened resistance is achieved. Our second aim is devoted to revealing the mechanisms used by larval trematodes in subverting snail defenses. We propose to test our earlier hypothesis that S. mansoni is a "stealth" parasite that largely avoids detection in the snail host whereas E. paraensei provokes a dramatic response but then relies on immunosuppressive tactics for survival. We will also examine how E. paraensei interferes with the innate resistance shown by the Salvador strain of B. glabrata to S. mansoni. The first part of our third aim is to develop molecular techniques to more precisely monitor the fate of S. mansoni sporocysts in snails. This work is a necessary prelude to the second part of this aim which is to understand an underappreciated yet important phenomenon that likely limits the number of schistosome-infected snails in nature, namely the inevitable failure of a significant percentage of schistosome infections in individual snails from populations otherwise considered to be susceptible. By using methods new to trematode-snail studies, we will gain broad and inclusive new overviews of these host-parasite interactions. Also, the tools generated will be useful for future studies of schistosome-snail interactions in the field. Our studies will also provide a valuable complement to the upcoming genome sequencing project for B. glabrata. [unreadable] [unreadable] [unreadable]